title: The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease.
abstract: Glucocorticoids are primary stress hormones necessary for life that regulate numerous physiologic processes in an effort to maintain homeostasis. Synthetic derivatives of these hormones have been mainstays in the clinic for treating inflammatory diseases, autoimmune disorders, and hematologic cancers. The physiologic and pharmacologic actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily of ligand-dependent transcription factors. Ligand-occupied GR induces or represses the transcription of thousands of genes through direct binding to DNA response elements, physically associating with other transcription factors, or both. The traditional view that glucocorticoids act through a single GR protein has changed dramatically with the discovery of a large cohort of receptor isoforms with unique expression, gene-regulatory, and functional profiles. These GR subtypes are derived from a single gene by means of alternative splicing and alternative translation initiation mechanisms. Posttranslational modification of these GR isoforms further expands the diversity of glucocorticoid responses. Here we discuss the origin and molecular properties of the GR isoforms and their contribution to the specificity and sensitivity of glucocorticoid signaling in healthy and diseased tissues.
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Oakley
authors.forename: John A
authors.initials: JA
authors.lastname: Cidlowski
mesh_terms: D017398:Alternative Splicing; D006801:Humans; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid
keywords: ACTH; AF; AP1; Activation function; Activator protein 1; Adrenocorticotropic hormone; CBG; Corticosteroid-binding globulin; DBD; DNA-binding domain; G protein–coupled receptor; GPCR; GR; GRE; Glucocorticoid receptor; Glucocorticoid-responsive element; LBD; Ligand-binding domain; MAPK; Mitogen-activated protein kinase; N-terminal transactivation domain; NF-κB; NTD; Negative glucocorticoid-responsive element; Nuclear factor κB; SEGRA; Selective glucocorticoid receptor agonist; glucocorticoid; glucocorticoid signaling; isoforms; nGRE; β(2)-Adrenergic receptor; β2AR